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4CMenB vaccine induces elite cross-protective human antibodies that compete with human factor H for binding to meningococcal fHbp
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 16, Iss 10, p e1008882 (2020)
- Publication Year :
- 2020
- Publisher :
- Public Library of Science, 2020.
-
Abstract
- Neisseria meningitidis serogroup B (MenB) is the leading cause of meningococcal meningitis and sepsis in industrialized countries, with the highest incidence in infants and adolescents. Two recombinant protein vaccines that protect against MenB are now available (i.e. 4CMenB and MenB-fHbp). Both vaccines contain the Factor H Binding Protein (fHbp) antigen, which can bind the Human Factor H (fH), the main negative regulator of the alternative complement pathway, thus enabling bacterial survival in the blood. fHbp is present in meningococcal strains as three main variants which are immunologically distinct. Here we sought to obtain detailed information about the epitopes targeted by anti-fHbp antibodies induced by immunization with the 4CMenB multicomponent vaccine. Thirteen anti-fHbp human monoclonal antibodies (mAbs) were identified in a library of over 100 antibody fragments (Fabs) obtained from three healthy adult volunteers immunized with 4CMenB. Herein, the key cross-reactive mAbs were further characterized for antigen binding affinity, complement-mediated serum bactericidal activity (SBA) and the ability to inhibit binding of fH to live bacteria. For the first time, we identified a subset of anti-fHbp mAbs able to elicit human SBA against strains with all three variants and able to compete with human fH for fHbp binding. We present the crystal structure of fHbp v1.1 complexed with human antibody 4B3. The structure, combined with mutagenesis and binding studies, revealed the critical cross-reactive epitope. The structure also provided the molecular basis of competition for fH binding. These data suggest that the fH binding site on fHbp v1.1 can be accessible to the human immune system upon immunization, enabling elicitation of human mAbs broadly protective against MenB. The novel structural, biochemical and functional data are of great significance because the human vaccine-elicited mAbs are the first reported to inhibit the binding of fH to fHbp, and are bactericidal with human complement. Our studies provide molecular insights into the human immune response to the 4CMenB meningococcal vaccine and fuel the rationale for combined structural, immunological and functional studies when seeking deeper understanding of the mechanisms of action of human vaccines.<br />Author summary Serogroup B meningococcus is a human pathogen causing meningitis and sepsis, especially in infants and adolescents. The recent development of two vaccines (4CMenB, MenB-fHbp) provides an opportunity to reduce disease incidence. One vaccine component is the factor H binding protein (fHbp), which exists in three main variants. On the meningococcal surface, fHbp recruits the human complement-downregulating factor H (fH), allowing the bacterium to evade the host immune system. Analyses of antibodies from vaccinated humans can yield insights into vaccine mechanisms of action. Recently, analyses of the response to 4CMenB vaccination identified thirteen new antibodies able to bind all three fHbp variants. We characterized all 13 antibodies. One of them, 4B3, is the first human antibody reported to effectively mediate bactericidal killing of meningococcal strains expressing each of the three fHbp variants and to compete with human fH for binding to fHbp. We present the three-dimensional structure of 4B3 complexed with fHbp, molecular details that explain how 4B3 can cross-react with all different fHbp variants and why it is so potent. This study provides a deeper understanding of 4CMenB vaccine-induced antibodies, and guidance for the rational design of antigens inducing broadly protective immunity.
- Subjects :
- Physiology
Complement System
Neisseria meningitidis
medicine.disease_cause
Pathology and Laboratory Medicine
Biochemistry
Epitope
Binding Analysis
Medical Conditions
Immune Physiology
Medicine and Health Sciences
Public and Occupational Health
Biology (General)
0303 health sciences
Vaccines
Immune System Proteins
Crystallography
biology
Physics
030302 biochemistry & molecular biology
Condensed Matter Physics
Vaccination and Immunization
Bacterial Pathogens
Infectious Diseases
Medical Microbiology
Complement Factor H
Physical Sciences
Crystal Structure
Antibody
Pathogens
Neisseria
Research Article
Adult
Infectious Disease Control
QH301-705.5
medicine.drug_class
Immunology
Meningococcal Vaccines
Meningococcal vaccine
Meningitis, Meningococcal
Monoclonal antibody
Research and Analysis Methods
Microbiology
Antibodies
03 medical and health sciences
Antigen
Bacterial Proteins
Virology
medicine
Genetics
Solid State Physics
Point Mutation
Humans
Molecular Biology
Microbial Pathogens
Chemical Characterization
030304 developmental biology
Antigens, Bacterial
Bacteria
Organisms
Biology and Life Sciences
Proteins
RC581-607
Complement system
Immune System
Mutation
biology.protein
Alternative complement pathway
Parasitology
Preventive Medicine
Immunologic diseases. Allergy
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 16
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....b62f489a3029dea30dd80973193e9414